Impact of hypertension and aging on postoperative delirium

Duke University, Durham NC

Investigators

Abstract

ABSTRACT Postoperative delirium is a frequent complication that follows surgical interventions and impairs recovery of many older adults. Delirium contributes to both acute and long-term complications, including mortality and co- morbidities that further reduce quality of life and increase healthcare costs, including the burden of newly diagnosed Alzheimer’s disease and related dementias (AD/ADRD). Hypertension is a common diagnosis for millions of older adults (65 years of age and older) and is a known risk factor for dementia with well-documented neurological implications, especially stroke. Although recent epidemiological evidence associates hypertension with delirium, the mechanisms whereby chronic hypertension contributes to postoperative delirium and long-term cognitive decline remain poorly understood. Our research demonstrates that blood-brain barrier (BBB) dysfunction and postoperative neuroinflammation are exacerbated in mice with Angiotensin II (AngII)-dependent hypertension. This pathological brain response to surgical stress is accompanied by upregulation of the Ang II type 1 receptor (AT1R) and induction of perivascular macrophages (PVMs) in the hippocampus. The overarching goal of this proposal is to ascertain the causal role of these targets as key contributors to vascular impairments in postoperative delirium and ensuing ADRD onset. Our primary objective is to elucidate the specific contributions of endothelial cells (ECs) and PVMs to surgery-induced neuroinflammation, BBB disruption, and delirium-like behavior in aging and hypertension. Our central hypothesis posits that BBB dysfunction in hypertension primes the neurovascular unit (NVU) by worsening border-associated immune activation and vascular dysfunction, thus exacerbating delirium-like behavior after orthopedic surgery and aging. Our aims will: 1) determine the effects of hypertension on postoperative neuroinflammation and cognitive outcomes with aging, 2) analyze the alterations in ECs and PVMs following hypertension and orthopedic surgery, and 3) identify the role of AT1R signaling in delirium superimposed on hypertension and with a microphysiological NVU platform. Our respective laboratories have established the feasibility for all these models and techniques. Our innovative approach incorporates novel transgenic mouse lines and advanced behavioral assays to longitudinally evaluate cognitive decline in hypertensive mice following surgery and aging. These models are integrated with a microphysiologic NVU platform using an optical transparent silicon membrane (μSiM-NVU) populated with human induced pluripotent stem cells (iPSCs) differentiated into the cell types that constitute the BBB to further identify signaling and key targets at the NVU. The rationale for the proposed research is that successful completion will expand our understanding of vascular risk factors and NVU dysfunction in hypertension and postoperative delirium. This knowledge is significant as it can identify potential therapeutic strategies to prevent delirium and subsequent ADRD in older and vulnerable patients.